In 1974, the Matthews family moved to Cambridge, England for a year before returning to New York, where his father died from lung cancer in 1977. Biographer Nevin Martell argues that Dave’s father’s death may be an impetus for his “carpe diem” lyrics. At some point while residing in New York, Matthews attended his first concert, when his mother took him to a performance by Pete Seeger. The family returned to Johannesburg in 1977.

Upon Matthews’ graduation from Damelin College high school in 1985, he was faced with conscription into the South African military just as civil disobedience to the practice was becoming widespread. As a Quaker (and consequently pacifist), Matthews left South Africa to avoid service.

Matthews moved to New York in 1986 where he worked for IBM for a short time, then joined his mother that same year in Charlottesville, Virginia, a town Matthews’ family had lived in before he was born. In Charlottesville, he became part of the local music community. Although Matthews had started playing the guitar at age nine, it was only in Charlottesville that he started performing publicly. Through a mutual friend, Nic Cappon, Matthews met local star (and future collaborator) Tim Reynolds. In time, Reynolds had Matthews join him on stage, and eventually Matthews was persuaded to record some of his own songs. This led to his first professional musical gig at a modern dance performance by the Miki Liszt Dance Company, based at McGuffey Art Center in Charlottesville, singing “Meaningful Love”, composed by John D’earth and Dawn Thompson. In 1991, he hatched the idea to form his own band. Prior to recording his first demo, Matthews bartended at Miller’s in Charlottesville.

After writing his first few songs, including “I’ll Back You Up”, “The Song that Jane Likes” and “Recently”, Matthews formed Dave Matthews Band in early 1991 with LeRoi Moore, Carter Beauford, Stefan Lessard, Peter Griesar (who left the band in 1993), and Boyd Tinsley while working at Miller’s. The band’s first show was on March 14, 1991, as part of a benefit for the Middle East Children’s Alliance at Trax Nightclub in Charlottesville.

Matthews’ older sister Anne, who lived in South Africa, was murdered by her husband in early 1994. Her husband subsequently died by suicide, on or around January 27 of that year. The event had a profound effect on Matthews’ outlook on life and was referenced in a few of his songs. On January 29, 1994, he performed with Tim Reynolds at the Wetlands in New York, where he dedicated that performance “to her [Anne’s] memory”. Dave Matthews Band’s Under the Table and Dreaming, released later that year, was dedicated to her. Anne Matthews was survived by her two children and they traveled to the United States following her death. Dave and his younger sister Jane (after whom the Dave Matthews Band song “The Song That Jane Likes” is named) took responsibility for the children’s upbringing.

Matthews focused primarily on songwriting and performances with the Dave Matthews Band from 1990 to 2003. DMB is an artistic blend of acoustic guitar, bass, sax, drums and fiddle music. In 1994, DMB signed with RCA Records. Since that period, he has occasionally ventured outside the band in various solo performances and records. Matthews sang on the track “Sing Along” on Blue Man Group’s second album The Complex in 2003. Later that year he released a solo album, Some Devil, which went platinum; its single, “Gravedigger”, won a Grammy Award in 2004. Dave Mathews drew motivation for this song from the long-running Monster Jam celebrity Grave Digger. To support the album, Matthews toured with a group of musicians (many of whom performed on “Some Devil”) under the name Dave Matthews & Friends.

Dave often collaborates with banjoist Béla Fleck. Fleck is the frontman and namesake of Béla Fleck and the Flecktones; Matthews appears as guest vocalist with the band on their 1998 release, Left of Cool. Both Fleck and the Flecktones’ bassist Victor Wooten have made numerous live appearances and in studio with the Dave Matthews Band. Wooten soloed in the second part of the Daniel Lanois song, “The Maker”, and also in “#41” on the 1998 live album Live in Chicago. The Flecktones also opened for DMB on several tours. Matthews performed a duet with Emmylou Harris on “My Antonia” on her 2000 album, Red Dirt Girl. They also appeared together on the musical television show CMT Crossroads, where the two performed Matthews’ “Gravedigger” and the folk song “Long Black Veil”, a song popularized by The Band.

In 1999, Matthews purchased more than ten acres of land in Albemarle County, Virginia, known as Blenheim Farm, to preserve its historical significance. He later decided to plant grapes on the property, since it is located within both the Virginia and Monticello viticultural areas. Blenheim Vineyards was founded in 2000, and currently produces 5,500 cases of wine per year, including their signature Petit Verdot and several special edition wines which have featured unique labels with drawings by Matthews himself.

Dave Matthews married longtime girlfriend Jennifer Ashley Harper in 2000. They have twin daughters, Stella Busina and Grace Anne, born August 15, 2001, and a son, August Oliver, born June 19, 2007. They reside in Seattle. In a 2001 interview, Matthews stated that he was agnostic. Matthews is also on the Farm Aid board of directors along with fellow musicians Willie Nelson, John Mellencamp and Neil Young, who raise money for family farmers in the United States.

Before he was known as a musician, Dave Matthews was an amateur actor, appearing onstage in several productions at Charlottesville’s Offstage Theatre and Live Arts theater in the early 1990s; the role for which he is best remembered is as a used car salesman in Offstage Theatre’s “Just Say No,” directed by John Quinn, co-starring Kylie Suture. He played Will Coleman in the 2003 adaptation of the novel Where the Red Fern Grows. In 2005 he played in Because of Winn-Dixie as Otis, a man who works at a pet store and plays guitar. In 2007, Matthews appeared briefly in the movie I Now Pronounce You Chuck and Larry, where he plays a homosexual salesman. In 2008, he appeared in another Adam Sandler movie, You Don’t Mess with the Zohan, as a racist redneck character named James. He also had a significant role in Lake City with Sissy Spacek and Troy Garity, in which he portrays the character “Red.” He was also in three 2011 movies, The Other Side with Giovanni Ribisi and Jason Lee, In the Woods, starring Debra Winger and Terrence Howard, and the Adam Sandler/Jennifer Aniston comedy Just Go with It where he played Nicole Kidman’s husband.

In 2007, Matthews guest-starred in the Fox medical-drama series House in the episode “Half-Wit”. He played a piano-playing musical savant who ended up having the two hemispheres of his brain severed from each other in order to recover from his epilepsy, but at the expense of his musical abilities. Dave had a piano double for the complex pieces, but played the simpler pieces himself. In the season one episode of House, “Love Hurts”, the song “Some Devil” can be heard playing at the end. In another episode, one of the tracks from Stand Up, “You Might Die Trying” was played in the season five episode, “Not Cancer”.

Matthews also supported Barack Obama for President in 2008, both in the primaries and in the general election. On April 6, 2008, he and Tim Reynolds played a concert titled “Change Rocks” at Indiana University to encourage students to register to vote. The tickets were distributed by the Obama campaign. Questions regarding his citizenship were answered by advertisements and videos on YouTube, where he says he is a “real American” and a “real Virginian,” stating that “real Virginians get out and vote.” Even though he was recently bereaved by the loss of band co-founder and saxophonist, LeRoi Moore on August 19, 2008, he and Tim Reynolds played for the Democratic National Convention delegates on Sunday, August 24 at Red Rocks, and again with Reynolds at the Virginia Commonwealth University, on October 26, 2008, among other places. Matthews has often supported environmental initiatives, such as biofuel availability and the fight against global climate change.

The fifth time Matthews appeared as musical guest on Saturday Night Live in November 2009 (which was also the fourth time the Dave Matthews Band appeared on the show), he made an appearance as Ozzy Osbourne in a skit called “The Mellow Show”. Bill Hader impersonated Matthews in the same skit.

On September 21, 2009, Matthews stated that some of President Barack Obama’s harsher critics were motivated by his race, and stated that he “sees it [racism] everywhere” in the United States. Matthews is also a strong supporter of gay rights and participated in “Love Unites Shepard Fairey Equality Project”, a gay marriage advocacy project.

Matthews played a cover of Neil Young’s song, “The Needle and the Damage Done” at the 2010 tribute, MusiCares Person of the Year honoring Young on January 29, 2010. The Dave Matthews Band opened for the Rolling Stones on their Bridges to Babylon Tour (1997–1998), and Matthews sang “Wild Horses”, and “Memory Motel” alongside vocalist Mick Jagger.

In 2011, Matthews collaborated with wine makers Steve Reeder and Sean McKenzie in creating the Dreaming Tree Wines.

In April 2012, Matthews was credited as producer on a documentary, “Last Call at the Oasis”, directed by Jessica Yu.

On May 10, 2012, Matthews entertained a sellout crowd at the Paramount Theatre in Seattle where President Obama was hosting a campaign fundraiser.

In early 2013, Matthews participated in a jam session at Blade Studios in Shreveport, Louisiana with Jakob Dylan, Charlie Sexton, Blade studios co-owner Brady Blade, and Sexton’s brother Will. This eventually led to the formation of a band called The Nauts with Matthews, Dylan, Blade, and the Sexton brothers as members. However, there has been no news regarding an album release since that jam session.

Matthews was also a cast member and performer in the popular music documentary, Before the Music Dies. In 2018, Matthews guest-starred on the Prime Video original series Pete the Cat as the voice of Gustavo’s father, a platypus.

On May 16, 2020, in the midst of the COVID-19 quarantine, Matthews appeared streaming on the virtual graduation ceremonies for the University of Virginia. He wished students his best and said, “…it is now your small opportunity to make the world a better place, as you see fit.” He then sang the song, “Singing from the Windows” while accompanying himself on an acoustic guitar.